Azacyclic systems

Emphasis is placed on simply substituted free bases. The problems of conformational equilibria in /V-alkylpiperidinium salts and N-quaternization reactions and the relationships of these to conformational equilibria in the free bases are not covered, since this area is a large one requiring separate treatment. In other relevant previous reviews, the topics include heterocyclic conformational analysis,3-7 interactions in azacyclic systems,8 the conformational analysis of piperidine,9 hexahydropyrimidines,10,11 hexahydropyri-dazines,12 quinolizidines,13 the conformational analysis of bi- and polycyclic... 

Further examples of the formation of bridged azacyclic systems from the reaction of (65) with aryl Ketones are illustrated by the conversion of indanone (66) into (67) with ammonium acetate in ethanol. 67... 

The synthesis of 2-azacycl[3.2.2]azine (imidazo[2.1.5-c /]-indolizine), 334, by Paudler et al. <1975JOC1210> (Scheme 97) is apparently the only successful synthesis to date, and is in effect a variant of the Vilsmeier-Haack-Arnold method of Scheme 90. All attempts to synthesize the ring system by cycloadditions to imidazo[l,5- ]pyridine have been unsuccessful. 

The stereoselective construction of nitrogen heterocycles remains a topic of intense synthetic interest [39]. Evans and Robinson described the combination of the stereospecific aUylic amination with ring-closing metathesis as a strategy for the constmction of mono- and disubstituted azacycles, which they demonstrated with the stereospecific construction of cis- and tra s-2,5-disubstituted pyrrolines [40]. Furthermore, this approach provided an ideal system for the determination of whether the enantiospecific rhodium-catalyzed aUyhc amination with an enantiomerically enriched nucleophile experiences a matched and a mismatched reaction manifold. 

The dendrobatid toxin 25 ID (18) has been synthesized by a new approach which utilizes an iminium-vinylsilane cyclization to produce the (Z)-6-alkylidene-indolizidine ring-system in a stereospecific manner. The key intermediate (19) was prepared from L-proline and converted into toxin 25 ID (18) by reaction with paraformaldehyde and (+)-camphor-10-sulphonic acid in refluxing ethanol. The method is potentially a general one for forming unsaturated azacyclic rings, and it provides a convenient route to the pumiliotoxin A alkaloids.7... 

The condensation of /3-aminoacrolein with (61a,c) leads to the corresponding polymethylene-bridged tpys (66b,d) in low yields. The same systems may be prepared more effectively by the condensation of enamines (65a-c) with formaldehyde and subsequent azacyclization of the intermediate 1,5-diketone (Scheme 12).64 A Hantzsch approach to (66b) has also been reported.67 Benzaldehyde, 4-substituted benzaldehydes, and various other aryl aldehydes can be treated with (65a) to afford 4 -aryl derivatives of (66b) in moderate yields.69 A 48% yield of the monomethylene-bridged (66a) has been... 

Initial studies focused on lanthanocene-based catalyst systems that proofed to be efficient in the exo-specific cyclization of terminal aminoalkenes to form five-, six-, and seven-membered azacycles (Scheme 2). The reactions are predictably faster for the formation of smaller five-membered rings and in the presence of em-dialkyl substituents [117]. An increasing metal ionic radius and a more open coordination sphere, for example, in onra-lanthanocenes, are also beneficial for higher cyclization rates [103]. A further increase in catalytic activity is observed when sterically more open and more electrophilic CGC 17 (Fig. 15) are applied [118]. 

An account of a method for the homologation of methyl esters, catalysed by a ruthenium-cobalt bimetallic system, may have some future synthetic potential. Six- and seven-membered heterocyclic enamino-esters (74) undergo ring-contraction to give five- and six-membered azacyclic esters (75) in 89-92% yield (Scheme 40). The reactions of dianions derived from carboxylic acids and esters have been reviewed. ... 

Fused Five and Six Ring Nitrogen Systems.—The acid catalysed reactions of alkyli-dene bisurethanes with conjugated dienes gave various azacyclic and azabicyclic molecules formed by 1,4 (or 1,6)-addition to the conjugated system by the acylimine (241). > In new work the first example of a formal 1,3-cycIoaddition during the reaction of (241) with dienes has been observed (Scheme 107). 

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